The present invention relates to bis-aryl ethers having anti-cancer activity, compositions containing such compounds and methods of use. Additionally, the compounds are derived from a fungal culture which is included in the present invention. The organism is described herein as well as culture techniques useful for the production of the microorganism and the compound.
The method of treating cancer which is described herein relates to cancers which are effected by raf and raf-inducible genes and proteins. The cancers which can be treated are primarily Raf mediated tumors. Raf, and in particular, c-raf, is an oncogene which is overexpressed in a wide variety of tumors.
The raf genes code for a family of proteins which can be oncogenically activated through N-terminal fusion, truncation or point mutations. Raf undergoes rapid phosphorylation in response to PDGF, EGF, insulin, thrombin, endothelin, acidic FGF, CSF1 or TPA, as well as in response to oncoproteins v-fms, v-src, v-sis, Hras and polyoma middle T antigen. The raf family of oncogenes encompasses human A-raf-1, B-raf-1 and C-raf-1. The A-raf-1 gene is located on chromosome Xp11.3 and is expressed in numerous tissues and tissue types. It encodes a cytosolic protein of approximately 68,000 daltons. The C-raf-1 gene is located on chromosome 3p25 in a chromosomal site that has been found to be altered in several epithelial cancers. The gene encodes a protein which is approximately 74,000 daltons.
There is evidence that raf genes function downstream of ras in the transduction of activation signals from the membrane to the nucleus. By inhibiting raf as described herein, diseases in which ras, raf and other oncogenes integral to the transduction pathway can be treated.
Antisense constructs which reduce cellular levels of c-Raf, and hence Raf activity, inhibit the growth of oncogene-transformed rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. Since inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals, these studies suggest that the antagonism of Raf is an effective means by which to treat cancers in which Raf plays a role.
Additionally, antisense Raf oligonucleotides are efficacious in nude mouse xenograft studies in vivo, further validating Raf as a target which can be inhibited to treat cancer. Monia, B. P., et al. Nature Medicine 2(6): 668-675 (1996).
Examples of cancers where Raf is implicated through overexpression, include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.